Bedrock Therapeutics, Inc., is developing a method of controlling the immunologic response to allogenic hematopoietic stem cell transplants (HSCT) with the aim of preventing ocular manifestations of graft vs host disease (OGvHD), which significantly lower the quality of life of afflicted patients. Over 20,000 patients receive allogenic HSCTs per year in the US to treat hematological disorders. Of these, an estimated 35-54%, or approximately 7,000-11,000 patients annually, develop OGvHD. OGvHD is a manifestation of chronic graft vs host disease. The most common clinical development of OGvHD is dry eye, or keratoconjunctivitis sicca, which leads to symptoms such as ocular irritation, pain, conjunctival redness, photophobia, and reduced visual acuity. The dry eye of OGvHD significantly reduces quality of life of HSCT patients and limits their daily activities. Therapies for OGvHD are largely ineffective (response rate of only 23% at 6 months) and are directed at reducing symptoms, control of chronic disease, and prevention of tissue damage. Treatments include the use of multiple daily applications of topical lubricants, calcineurin inhibitors, corticosteroids, autologous serum, in addition to the use of bandage contact lenses, limbal or amnion membrane transplantation, and/or systemic immunosuppressants. Despite these treatments the therapeutic response is poor resulting in significantly reduced visual function and thus a large unmet need for effective treatment of OGvHD. Given the considerable number of HSCT performed annually in the US and the high incidence of OGvHD there is a critical need for an effective and practical means of treatment of OGvHD. Bedrock TherapeuticsÂ’ strategy for treatment of OGvHD is based on the immunomodulatory activities of Human Leukocyte Antigen G (HLA-G) proteins, which are natural proteins that act to prevent maternal rejection of the developing fetus. Our innovative optimized gene therapy methodology relies on use of adeno-associated virus (AAV) to deliver a novel engineered, HLA-G based, single chain immunomodulatory (scIM) protein to modulate the immunologic response following HSCT. To develop a single drug to ease regulatory development, Bedrock has engineered a functional scIM protein (BDRK#004) whose conformation mimics a beta2-microglubulin (B2M) bound HLA-G dimer complex whose cDNA can be packaged and delivered using a single AAV8 vector packaged with a self-complementary genome, which are enhanced >10-fold in transduction efficiency compared to single-strand AAV genomes. This innovative therapeutic will fulfill the unmet need for a safe and effective single dose drug for OGvHD and possibly other immune-mediated ocular diseases, such as keratitis, diabetic retinopathy, and age-related macular degeneration. Bedrock Therapeutics proposes in this phase I application to evaluate its single dose scIM drug formulation for tolerability and function on primary human T cells (Aim 1) and its efficacy, safety, and biodistribution in our murine model of OGvHD (Aim 2). Public Health Relevance Statement Project Narrative Bedrock Therapeutics has developed a single dose, gene therapy technology that relies on use of adeno- associated virus to deliver a novel engineered, HLA-G based, single chain immunomodulatory protein to control the immunologic response to allogenic hematopoietic stem cell transplants with the aim of preventing ocular manifestations of graft vs host disease.
Project Terms: Dependovirus ; Adeno-Associated Viruses ; Dependoparvovirus ; adeno associated virus group ; Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; amnion ; Bandage ; Complementary DNA ; cDNA ; Cells ; Cell Body ; Chronic Disease ; Chronic Illness ; chronic disorder ; Clinical Research ; Clinical Study ; Codon Nucleotides ; Codon ; conjunctiva ; Contact Lenses ; Cornea ; corneal ; Cyclosporine ; Ciclosporin ; CsA ; Cyclosporin A ; Cyclosporine A ; Sandimmun ; SangCya ; neoral ; sandimmune ; Diabetic Retinopathy ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Dry Eye Syndromes ; Dry eye disease ; Keratoconjunctivitis Sicca ; Engineering ; Fetal Development ; Developing fetus ; Fibrosis ; gene therapy ; DNA Therapy ; Gene Transfer Clinical ; Genetic Intervention ; gene-based therapy ; genetic therapy ; genomic therapy ; Genome ; Goals ; graft vs host disease ; GvHD ; Homologous Wasting Disease ; Runt Disease ; graft versus host disease ; graft vs. host disease ; Hematological Disease ; Blood Diseases ; Hematologic Diseases ; Hematological Disorder ; blood disorder ; HLA Antigens ; HL-A Antigens ; Human Leukocyte Antigens ; Leukocyte Antigens ; Human ; Modern Man ; Human Activities ; Immunosuppression ; Immunosuppression Effect ; Immunosuppressive Effect ; immune suppression ; Immunosuppressive Agents ; Immunosuppressants ; Immunosuppressive drug ; Immunosuppressive treatment ; immune suppressive agent ; immune suppressor ; immunosuppressive substance ; immunosuppressor ; In Vitro ; Incidence ; Inflammation ; Integral Membrane Protein ; Intrinsic Membrane Protein ; Transmembrane Protein ; Transmembrane Protein Gene ; Keratitis ; Laboratories ; Lacrimal gland structure ; Lacrimal Glands ; meibomian gland ; Tarsal Glands ; Methods ; Methodology ; Molecular Conformation ; Molecular Configuration ; Molecular Stereochemistry ; conformation ; conformational state ; Mus ; Mice ; Mice Mammals ; Murine ; New Zealand ; Pain ; Painful ; Patients ; Production ; Proteins ; Quality of life ; QOL ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Safety ; Saline ; Saline Solution ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Technology ; Tissues ; Body Tissues ; Transplantation ; transplant ; Up-Regulation ; Upregulation ; Uvea ; Ciliary Body and Choroid Iris ; Tunica Vasculosa of Eyeball ; Uveal Tract ; Vascularization ; Viral Genome ; virus genome ; Virion ; Virus Particle ; Vision ; Sight ; visual function ; Visual Acuity ; Work ; Photophobia ; Light Sensitivity ; GTP-Binding Proteins ; G-Proteins ; GTP-Regulatory Proteins ; Guanine Nucleotide Coupling Protein ; Guanine Nucleotide Regulatory Proteins ; Mediating ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; base ; improved ; Phase ; Evaluation ; Myofibroblast ; Serum ; Blood Serum ; Visual ; Age related macular degeneration ; Age-Related Maculopathy ; age related macular dystrophy ; senile macular disease ; Hematopoietic Stem Cell Transplantation ; HSC transplantation ; Hematopoietic Stem Cell Transplant ; AlamarBlue ; Alamar Blue ; Lubricants ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; dry eye ; eye dryness ; Infiltration ; Redness ; cicatrix corneal ; corneal fibrosis ; corneal scar ; transplant patient ; Transplant Recipients ; Immunes ; Immune ; Complex ; Autologous ; irritation ; limbal ; Drug Formulations ; Lytotoxicity ; cytotoxicity ; dimer ; experience ; membrane structure ; Membrane ; Isoforms ; Protein Isoforms ; Toxicities ; Toxic effect ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; novel ; disease prevention ; disorder prevention ; Topical Drug Administration ; administer topically ; apply topically ; deliver topically ; topical administration ; topical delivery ; topical drug application ; topical treatment ; topically administered ; topically applied ; topically delivered ; topically treated ; treat topically ; Topical application ; disorder model ; Disease model ; Prevention ; Chronic GVHD ; chronic graft vs host disease ; chronic graft vs. host disease ; chronic graft versus host disease ; Modeling ; response ; HLA-G1 ; T-Cell Proliferation ; HLA-G5 ; preventing ; prevent ; Dose ; Symptoms ; Duct Epithelium ; Ductal Epithelium ; Allogenic ; Cellular Infiltration ; Eye Development ; eye morphogenesis ; ocular development ; Characteristics ; Development ; developmental ; Immunomodulators ; IMiD ; Immune modulatory therapeutic ; immune modulating agents ; immune modulating drug ; immune modulating therapeutics ; immune modulators ; immune modulatory agents ; immune modulatory drugs ; immunomodulating agents ; immunomodulatory agents ; immunomodulatory drugs ; immunomodulatory therapeutics ; lacrimal ; intravitreal injection ; Calcineurin inhibitor ; Calcineurin antagonist ; preclinical study ; pre-clinical study ; autoimmune uveitis ; vector ; neovascularization ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; Biodistribution ; ocular surface ; innovation ; innovate ; innovative ; transduction efficiency ; adeno-associated viral vector ; AAV vector ; adeno-associated virus vector ; mouse model ; murine model ; treatment response ; response to treatment ; therapeutic response ; treatment strategy ; effective therapy ; effective treatment ; DNA cassette ; enhancer cassette ; expression cassette ; gene cassette ; genetic cassette ; integration cassette ; promoter cassette ; reporter cassette ; resistance cassette ; selectable cassette ; selection cassette ; stop cassette ; transcription cassette ; transcriptional cassette ; transgene cassette ; reduce symptoms ; alleviate symptom ; ameliorating symptom ; decrease symptom ; fewer symptoms ; relieves symptoms ; symptom alleviation ; symptom reduction ; symptom relief ; clinical development ; Injections ; Tumor-infiltrating immune cells ; Immune infiltrates ; T cell infiltration ; T cell tumor trafficking ; immune cell infiltrate ; immune infiltration ; intratumoral immune cell ; tumor immune cell ;
